In contrast, for nonulcer bleeds, the PAF was slightly increased for gastrointestinal cancer, alcohol, anticoagulants, and selective serotonin reuptake inhibitors. The crude ORs were re-estimated for medications after excluding cases with nonmedication risk factors and these are

shown in Supplementary Table 2. NSAID use was strongly associated with bleeding, with an OR of 1.67, and this increased to 2.80 with the exclusion of nonmedication risk factors. The corresponding adjusted ORs associated with NSAIDs were selleck chemical 1.59 with nonmedication risk factors included and 1.73 without. Altering the exposure exclusion window for NSAIDs to 30 days rather than 60 days before the bleed slightly increased the effect of NSAIDS, but had only a minimal effect on the other results, including comorbidity (see Supplementary Table 3). Restricting the analysis to those older than 65 years old increased the proportion of cases attributable to the combined effect of all exposures from 48% to 63%, and reduced the additional proportion of cases attributable to nongastrointestinal comorbidity from 19.8% to 16.1%. Re-estimating the model using multiple imputation for missing alcohol and smoking status (modeled as binary exposures) slightly reduced the PAF associated with comorbidity from 22.9% to 22.4%, but when alcohol and smoking Doxorubicin molecular weight status

were omitted from the model, the PAF was almost unaltered at 22.2%. Finally, the full model was re-estimated for each component of the Charlson Index (Table 6). The contribution of these individual comorbidities was minimal in comparison with their combined weighted effect in the Charlson Index in the main analysis. This

study has demonstrated that a combined measure of nongastrointestinal comorbidity is a significant independent predictor of upper GIB, even after accounting for all other recognized and measured risk factors. In addition, dipyridamole it explained a greater proportion of the burden of bleeding than any other risk factor in the population. The effect of this combined measure of nongastrointestinal comorbidity was far in excess of that which would be expected from its constituent diseases. The association of comorbidities with upper GIB has been studied previously, but only in smaller secondary care surveys with comorbidity as a confounder and not as the primary exposure. We searched PubMed using variants of comorbidity, etiology, causality, risk factors, and gastrointestinal hemorrhage; however, no studies were identified that set out to address the question of our article. Studies were most frequently designed to measure the association of a single medication while adjusting for any confounding by comorbidity.21 and 22 Two studies assessed a larger range of medications in cross-sectional hospital-based surveys.

46 The rationale for pulsed therapy was mainly driven by the concerns about the emergence of resistance with long-term continuous use of antibiotics. Pulsed therapy would allow time for the normal flora to recover and therefore potentially prevent or delay the emergence of resistant strains.33 Moxifloxacin was selected for the study

based on its potent in vitro activity against the major COPD pathogens, excellent penetration into respiratory tissues, high oral bioavailability and proven efficacy in increasing the exacerbation-free interval. 46, 55 and 88 Pulsed therapy with moxifloxacin was found to significantly reduce the risk of an exacerbation by 25% (per protocol population) in patients with moderate-to-severe COPD, while in a post-hoc analysis, this reduction was 45% in patients with purulent/mucopurulent sputum at randomisation. 46 These studies suggest that long-term antibiotic Selleckchem Regorafenib treatment in COPD patients reduces exacerbation frequency, though evidence for a reduction in inflammation is limited. Long-term antibiotic therapy appears to be well tolerated, though not all studies reported safety.81 Nevertheless, gastrointestinal events were more common in patients

receiving pulsed moxifloxacin versus placebo (4.7% vs 0.7%, respectively)46 and 12-month azithromycin treatment resulted in a higher incidence of hearing loss (25% of patients with azithromycin vs 20% of patients with placebo).45 Although long-term (daily) azithromycin treatment led to a decrease in the incidence of colonisation by respiratory pathogens, such treatment was Selleck Z-VAD-FMK also associated with an increased prevalence of macrolide-resistant bacteria colonising the airways, though there was no evidence that this colonisation increased the number of exacerbations or the incidence of pneumonia.45 No relevant resistance was reported in

the study with pulsed (with one cycle lasting for only 5 days in every 8 weeks) moxifloxacin treatment,46 Acyl CoA dehydrogenase while in others resistance development was minimal85 and 86 or not reported.81 and 82 Although the studies described above suggest that use of prophylactic oral antibiotic therapy is well tolerated, some macrolides are known to be proarrhythmic and even 5-day treatment with azithromycin has been associated with a small absolute increase in cardiovascular deaths.89 This issue, coupled with concerns of increased antibiotic resistance, indicates that such treatment should be reserved for those with severe COPD who experience frequent exacerbations requiring multiple antibiotic treatments, in spite of adequate management of their COPD with standard treatments.90 Use of inhaled antibiotics is expected to have a future role in the long-term management of patients with COPD since this route of administration has the ability to target drug delivery directly to respiratory tract.